Coral reefs can experience extreme salinity changes, particularly hypo-salinity, as a result of storms, heavy rainy seasons (e.g., monsoons), and coastal runoff. Field and laboratory observations have documented that corals exposed to hypo-saline conditions can undergo extensive bleaching and mortality. There is controversy in the literature as to whether hypo-saline conditions induce a pathological response in corals, and if there is a relationship between decreasing salinity treatment and pathological responses. To test the hypothesis that hypo-salinity exposure does not have a pathological effect on coral, we used histological and cellular diagnostic methods to characterize the pathology in hypo-salinity-exposed corals. Colonies of Stylophora pistillata were exposed to five salinity concentrations [39 parts per thousand (ppt), 32 ppt, 28 ppt, 24 ppt, and 20 ppt] that may realistically occur on a reef. Histological examination indicated an increasing severity of pathomorphologies associated with decreasing salinity, including increased tissue swelling, degradation and loss of zooxanthellae, and tissue necrosis. Pulse-amplitude modulated chlorophyll fluorimetry kinetics demonstrated a decreasing photosynthetic efficiency with decreasing salinity conditions. Cytochrome P450 levels were affected by even slight changes in salinity concentration suggesting that detoxification pathways, as well as several endocrine pathways, may be adversely affected. Finally, these studies demonstrated that hypo-saline conditions can induce an oxidative-stress response in both the host and in its algal symbiont, and in so doing, may synergistically increase oxidative-stress burdens. As with other types of environmental stresses, exposure to hypo-saline conditions may have long-term consequences on coral physiology.